title: Intranasal formulation of erythropoietin (EPO) showed potent protective activity against amyloid toxicity in the Aβ₂₅₋₃₅ non-transgenic mouse model of Alzheimer's disease.
abstract: Erythropoietin (EPO) promotes neurogenesis and neuroprotection. We here compared the protection induced by two EPO formulations in a rodent model of Alzheimer's disease (AD): rHu-EPO and a low sialic form, Neuro-EPO. We used the intracerebroventricular administration of aggregated Aβ₂₅₋₃₅ peptide, a non-transgenic AD model. rHu-EPO was tested at 125-500 µg/kg intraperitoneally and Neuro-EPO at 62-250 µg/kg intranasally (IN). Behavioural procedures included spontaneous alternation, passive avoidance, water-maze and object recognition, to address spatial and non-spatial, short- and long-term memories. Biochemical markers of Aβ₂₅₋₃₅ toxicity in the mouse hippocampus were examined and cell loss in the CA1 layer was determined. rHu-EPO and Neuro-EPO led to a significant prevention of Aβ₂₅₋₃₅-induced learning deficits. Both EPO formulations prevented the induction of lipid peroxidation in the hippocampus, showing an antioxidant activity. rHu-EPO (250 µg/kg) or Neuro-EPO (125 µg/kg) prevented the Aβ₂₅₋₃₅-induced increase in Bax level, TNFα and IL-1β production and decrease in Akt activation. A significant prevention of the Aβ₂₅₋₃₅-induced cell loss in CA1 was also observed. EPO is neuroprotective in the Aβ₂₅₋₃₅ AD model, confirming its potential as an endogenous neuroprotection system that could be boosted for therapeutic efficacy. We here identified a new IN formulation of EPO showing high neuroprotective activity. Considering its efficacy, ease and safety, IN Neuro-EPO is a new promising therapeutic agent in AD.
authors.affiliation: 1University of Montpellier 2, Montpellier, France.
authors.forename: Tangui
authors.initials: T
authors.lastname: Maurice
authors.forename: Muhammad-Hariri
authors.initials: MH
authors.lastname: Mustafa
authors.forename: Catherine
authors.initials: C
authors.lastname: Desrumaux
authors.forename: Emeline
authors.initials: E
authors.lastname: Keller
authors.forename: Gaëlle
authors.initials: G
authors.lastname: Naert
authors.forename: María
authors.initials: M
authors.lastname: de la C García-Barceló
authors.forename: Yamila
authors.initials: Y
authors.lastname: Rodríguez Cruz
authors.forename: Julío César
authors.initials: JC
authors.lastname: Garcia Rodríguez
mesh_terms: D000281:Administration, Intranasal; D000544:Alzheimer Disease / Q000517:prevention & control*; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors* / Q000633:toxicity; D000818:Animals; D002452:Cell Count; D002626:Chemistry, Pharmaceutical; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004921:Erythropoietin / Q000008:administration & dosage* / Q000494:pharmacology* / Q000627:therapeutic use; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D053583:Interleukin-1beta / Q000378:metabolism; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use*; D010446:Peptide Fragments / Q000037:antagonists & inhibitors* / Q000633:toxicity; D017467:Receptors, Erythropoietin / Q000378:metabolism; D021641:Recognition, Psychology / Q000187:drug effects; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D012153:Retention, Psychology / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; C587672:IL1B protein, mouse; D053583:Interleukin-1beta; D018696:Neuroprotective Agents; D010446:Peptide Fragments; D017467:Receptors, Erythropoietin; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; C074636:amyloid beta-protein (25-35); D004921:Erythropoietin
keywords: Alzheimer’s disease; Erythopoietin; intranasal formulation; learning and memory; neuroprotection